The majority of cancer deaths are the result of tumor cells metastasizing beyond their original niche [1]. Disseminated disease is difficult to resect and frequently more heterogeneous than the primary tumor. Moreover, acquisition of drug resistance further complicates effective therapeutic approaches. In ovarian cancer in particular, late stage at discovery and drug resistance are major challenges [2,3], resulting in five year survival rates of approximately 25% [2,4]. Thus, a novel therapeutic addressing both metastasis and drug resistance is urgently needed.
A promising target for such an approach is the transcription factor TWIST1. TWIST1 expression and activity is essential in early development but suppressed in adults. However, many cancers reactivate TWIST1 expression [5-7]. In both the developmental and cancer settings, TWIST1 drives an epithelial to mesenchymal transition (EMT), in which cells alter their surface proteins to facilitate migration and invasion [6]. Enhanced cellular motility in turn gives rise to mesodermal tissues in embryogenesis and to metastases in the cancer setting [6,7]. Furthermore, TWIST1 has been implicated in a number of pro-progression phenotypes in cancer, including angiogenesis [8], increased cancer cell stemness [9,10], and survival signaling [11] (FIG. 1A).
TWIST1 has well-characterized transcription factor activity; its dimerization partners and binding site within target promoters have been elucidated previously [12,13]. Recently, more attention has been given to the Twist box or WR domain, comprised of the C-terminal twenty amino acids of the protein (FIG. 1B). The TWIST1 gene is well conserved evolutionarily, but this is especially true for the WR domain; 100% homology is preserved from human to xenopus (FIG. 1C). We have previously shown that the WR domain mediates a binding interaction between TWIST1 and the NF-κB subunit RELA, and that this interaction leads to transcriptional upregulation of the inflammatory cytokine interleukin 8 (IL-8) in a manner independent of TWIST1-DNA binding [14]. Furthermore, Piccinin et al. demonstrated a binding interaction between the WR domain and the C-terminus of the tumor suppressor p53, which led to p53 degradation [15]. Recently, it was revealed that the WR domain can also bind to the WR domain of a nearby TWIST1 heterodimer, thereby creating higher order complexes required for proper transcriptional regulation [13]. This finding sheds light on the discovery that altered TWIST1-mediated transcription was responsible for the inability of prostate cancer cells expressing truncated alleles of TWIST1 to metastasize in an in vivo model [16].
There is a need in the art for novel methods of treating cancer. The disclosure is directed to this, as well as other, important ends.